Pub Date : 2024-08-06DOI: 10.1007/s00262-024-03785-4
Jaewon Cho, Nara Tae, Yujeong Song, Chae-Won Kim, Seung-Joo Lee, Jae-Hee Ahn, Kwang-Ho Lee, Byung-Hyun Lee, Byung Soo Kim, Sun-Young Chang, Dae Hee Kim, Hyun-Jeong Ko
Anti-cluster of differentiation (CD) 3 × α programmed death-ligand 1 (PD-L1) bispecific T-cell engager (BsTE)-bound T-cells (BsTE:T) are a promising new cancer treatment agent. However, the mechanisms of action of bispecific antibody-armed activated T-cells are poorly understood. Therefore, this study aimed to investigate the anti-tumor mechanism and efficacy of BsTE:T. The BsTE:T migration was assessed in vivo and in vitro using syngeneic and xenogeneic tumor models, flow cytometry, immunofluorescence staining, transwell migration assays, microfluidic chips, Exo View R100, western blotting, and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 technology. In murine B16 melanoma, MC38 colon cancer, and human multiple myeloma cells, BsTE:T exhibited superior tumor elimination relative to that of T-cells or BsTE alone. Moreover, BsTE:T migration into tumors was significantly enhanced owing to the presence of PD-L1 in tumor cells and secretion of PD-L1-containing exosomes. Furthermore, increased infiltration of CD44highCD62Llow effector memory CD8+ T-cells into tumors was closely associated with the anti-tumor effect of BsTE:T. Therefore, BsTE:T is an innovative potential anti-tumor therapy, and exosomal PD-L1 plays a crucial role both in vitro and in vivo in the anti-tumor activity of BsTE:T.
抗分化簇(CD)3 × α程序性死亡配体 1(PD-L1)双特异性 T 细胞吸引子(BsTE)结合 T 细胞(BsTE:T)是一种很有前景的新型癌症治疗药物。然而,人们对双特异性抗体修饰的活化 T 细胞的作用机制知之甚少。因此,本研究旨在探讨 BsTE:T 的抗肿瘤机制和疗效。本研究利用合成肿瘤模型和异种肿瘤模型、流式细胞术、免疫荧光染色、Transwell迁移试验、微流控芯片、Exo View R100、Western印迹和聚类规则间距短回文重复序列(CRISPR)/CRISPR相关蛋白9技术,对BsTE:T的体内和体外迁移进行了评估。在小鼠 B16 黑色素瘤、MC38 结肠癌和人类多发性骨髓瘤细胞中,BsTE:T 的肿瘤消除效果优于 T 细胞或 BsTE 本身。此外,由于肿瘤细胞中存在 PD-L1 和分泌含 PD-L1 的外泌体,BsTE:T 向肿瘤的迁移明显增强。此外,CD44highCD62Llow效应记忆CD8+T细胞浸润肿瘤的增加与BsTE:T的抗肿瘤作用密切相关。因此,BsTE:T 是一种具有创新潜力的抗肿瘤疗法,外泌体 PD-L1 在 BsTE:T 的体外和体内抗肿瘤活性中发挥着关键作用。
{"title":"The expression of PD-L1 on tumor-derived exosomes enhances infiltration and anti-tumor activity of αCD3 × αPD-L1 bispecific antibody-armed T cells.","authors":"Jaewon Cho, Nara Tae, Yujeong Song, Chae-Won Kim, Seung-Joo Lee, Jae-Hee Ahn, Kwang-Ho Lee, Byung-Hyun Lee, Byung Soo Kim, Sun-Young Chang, Dae Hee Kim, Hyun-Jeong Ko","doi":"10.1007/s00262-024-03785-4","DOIUrl":"10.1007/s00262-024-03785-4","url":null,"abstract":"<p><p>Anti-cluster of differentiation (CD) 3 × α programmed death-ligand 1 (PD-L1) bispecific T-cell engager (BsTE)-bound T-cells (BsTE:T) are a promising new cancer treatment agent. However, the mechanisms of action of bispecific antibody-armed activated T-cells are poorly understood. Therefore, this study aimed to investigate the anti-tumor mechanism and efficacy of BsTE:T. The BsTE:T migration was assessed in vivo and in vitro using syngeneic and xenogeneic tumor models, flow cytometry, immunofluorescence staining, transwell migration assays, microfluidic chips, Exo View R100, western blotting, and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 technology. In murine B16 melanoma, MC38 colon cancer, and human multiple myeloma cells, BsTE:T exhibited superior tumor elimination relative to that of T-cells or BsTE alone. Moreover, BsTE:T migration into tumors was significantly enhanced owing to the presence of PD-L1 in tumor cells and secretion of PD-L1-containing exosomes. Furthermore, increased infiltration of CD44<sup>high</sup>CD62L<sup>low</sup> effector memory CD8<sup>+</sup> T-cells into tumors was closely associated with the anti-tumor effect of BsTE:T. Therefore, BsTE:T is an innovative potential anti-tumor therapy, and exosomal PD-L1 plays a crucial role both in vitro and in vivo in the anti-tumor activity of BsTE:T.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1007/s00262-024-03769-4
Qi Zhao, Xi Su, Jiao Xue, Yandong Liu, Jiaxing Zhu, Xuwei Cai, Songbing Qin
There is growing evidence to suggest that radiotherapy might enhance the efficacy of immunotherapy. This study aimed to assess the possibility of KN046, a bispecific antibody targeting PD-L1 and CTLA-4, combined with chemotherapy and palliative radiotherapy for advanced esophageal squamous cell carcinoma (ESCC). In this open-label, phase Ib trial, patients with advanced ESCC were administered chemotherapy with palliative radiotherapy, and KN046 in the predefined escalation dosages of 1, 3, or 5 mg/kg (every 3 weeks during chemotherapy cycles and every 2 weeks during KN046 maintenance). The chemotherapy regimen constituted cisplatin (75 mg/m2 i.v., d1) and paclitaxel (135-175 mg/m2 ivgtt., d1). Radiotherapy specifics, including site, timing, dose, and fragmentation pattern, were at the investigator's discretion. The primary outcome was dose-limiting toxicity (DLT). From May 2019 to April 2021, 25 patients were enrolled across the dosage groups: 3 in 1 mg/kg, 12 in 3 mg/kg, and 10 in 5 mg/kg. No DLT was observed during the dose escalation. The objective response rate was 41.7% (95%CI 22.1-63.4), while the disease control rate was 87.5% (95%CI 67.6-97.3). At a median follow-up of 11.8 months, the median progression-free survival was 7.8 months (95%CI 5.2-9.7) and median overall survival was 15.9 months (95%CI 8.4-NE). Serious adverse events were reported in 48.0% of patients, predominantly leukopenia (16%), immune-mediated enterocolitis (12%), immune-mediated pneumonitis (8%), and neutropenia (8%). Combining KN046 with chemotherapy and palliative radiotherapy might be feasible, showing a favorable safety profile and notable efficacy in advanced ESCC patients.
{"title":"First-line treatment with KN046, chemotherapy and palliative radiotherapy for advanced esophageal squamous cell carcinoma: an open-label, dose escalation, and dose expansion phase Ib trial.","authors":"Qi Zhao, Xi Su, Jiao Xue, Yandong Liu, Jiaxing Zhu, Xuwei Cai, Songbing Qin","doi":"10.1007/s00262-024-03769-4","DOIUrl":"10.1007/s00262-024-03769-4","url":null,"abstract":"<p><p>There is growing evidence to suggest that radiotherapy might enhance the efficacy of immunotherapy. This study aimed to assess the possibility of KN046, a bispecific antibody targeting PD-L1 and CTLA-4, combined with chemotherapy and palliative radiotherapy for advanced esophageal squamous cell carcinoma (ESCC). In this open-label, phase Ib trial, patients with advanced ESCC were administered chemotherapy with palliative radiotherapy, and KN046 in the predefined escalation dosages of 1, 3, or 5 mg/kg (every 3 weeks during chemotherapy cycles and every 2 weeks during KN046 maintenance). The chemotherapy regimen constituted cisplatin (75 mg/m<sup>2</sup> i.v., d1) and paclitaxel (135-175 mg/m<sup>2</sup> ivgtt., d1). Radiotherapy specifics, including site, timing, dose, and fragmentation pattern, were at the investigator's discretion. The primary outcome was dose-limiting toxicity (DLT). From May 2019 to April 2021, 25 patients were enrolled across the dosage groups: 3 in 1 mg/kg, 12 in 3 mg/kg, and 10 in 5 mg/kg. No DLT was observed during the dose escalation. The objective response rate was 41.7% (95%CI 22.1-63.4), while the disease control rate was 87.5% (95%CI 67.6-97.3). At a median follow-up of 11.8 months, the median progression-free survival was 7.8 months (95%CI 5.2-9.7) and median overall survival was 15.9 months (95%CI 8.4-NE). Serious adverse events were reported in 48.0% of patients, predominantly leukopenia (16%), immune-mediated enterocolitis (12%), immune-mediated pneumonitis (8%), and neutropenia (8%). Combining KN046 with chemotherapy and palliative radiotherapy might be feasible, showing a favorable safety profile and notable efficacy in advanced ESCC patients.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1007/s00262-024-03782-7
Changhee Park, Koung Jin Suh, Se Hyun Kim, Kyung-Hun Lee, Seock-Ah Im, Min Hwan Kim, Joohyuk Sohn, Jae Ho Jeong, Kyung Hae Jung, Kyoung Eun Lee, Yeon Hee Park, Hee-Jun Kim, Eun Kyung Cho, In Sil Choi, Seung-Jae Noh, Inkyung Shin, Dae-Yeon Cho, Jee Hyun Kim
Background: Biomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863).
Methods: We analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise.
Findings: Analyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months).
Interpretation: Genomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.
背景预测乳腺癌患者对免疫疗法和化疗联合疗法反应的生物标志物尚未确立。在本研究中,我们报告了对参加艾瑞布林和尼夫单抗联合治疗HER-2阴性转移性乳腺癌(MBC)II期临床试验(KORNELIA试验,NCT04061863)的患者的预处理肿瘤组织进行的探索性基因组学和转录组学分析:我们分析了基于基因组(n = 76)和转录组数据(n = 58)的肿瘤分子特征与疗效之间的关联。无进展生存期(PFS)≥6个月的患者定义为PFS6应答者,否则定义为PFS6非应答者:对肿瘤突变负荷(TMB)的分析表明,肿瘤突变负荷对疗效有有利影响,而与同源重组缺陷(HRD)相关的几项分析表明,肿瘤突变负荷对疗效有潜在的负面影响。携带TP53突变的患者的PFS6率和PFS明显较低,这与PFS6无反应者中细胞周期相关特征的富集有关。高抗原呈递基因组富集得分(≥中位数)与较长的PFS显著相关。长期应答者(≥ 18 个月)的新生 B 细胞和浆细胞比例明显更高:解读:包括TMB、HRD和TP53突变在内的基因组特征以及与免疫细胞特征和细胞周期相关的转录组特征可区分应答者。我们的研究结果为进一步探索这些肿瘤的联合治疗方案及其生物标志物提供了启示。
{"title":"Genomic and transcriptomic profiles associated with response to eribulin and nivolumab combination in HER-2-negative metastatic breast cancer.","authors":"Changhee Park, Koung Jin Suh, Se Hyun Kim, Kyung-Hun Lee, Seock-Ah Im, Min Hwan Kim, Joohyuk Sohn, Jae Ho Jeong, Kyung Hae Jung, Kyoung Eun Lee, Yeon Hee Park, Hee-Jun Kim, Eun Kyung Cho, In Sil Choi, Seung-Jae Noh, Inkyung Shin, Dae-Yeon Cho, Jee Hyun Kim","doi":"10.1007/s00262-024-03782-7","DOIUrl":"10.1007/s00262-024-03782-7","url":null,"abstract":"<p><strong>Background: </strong>Biomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863).</p><p><strong>Methods: </strong>We analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise.</p><p><strong>Findings: </strong>Analyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months).</p><p><strong>Interpretation: </strong>Genomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><strong>Background: </strong>HHLA2 (human endogenous retrovirus-H long terminal repeat-associating protein 2) represents a recently identified member of the B7 immune checkpoint family, characterized by limited expression in normal tissues but notable overexpression in various cancer types. Nevertheless, the precise function and interaction with immune cells remain poorly understood, particularly in laryngeal squamous cell carcinoma (LSCC). This investigation endeavored to elucidate the biological significance of HHLA2 within the tumor microenvironment of human LSCC tissues and delineate the clinical relevance and functional roles of HHLA2 in LSCC pathogenesis.</p><p><strong>Methods: </strong>Through multiplexed immunohistochemistry analyses conducted on tissue microarrays sourced from LSCC patients (n = 72), the analysis was executed to assess the expression levels of HHLA2, density and spatial patterns of CD68<sup>+</sup>HLA-DR<sup>+</sup>CD163<sup>-</sup> (M1 macrophages), CTLA-4<sup>+</sup>CD4<sup>+</sup>FoxP3<sup>+</sup> (CTLA-4<sup>+</sup>Treg cells), CTLA-4<sup>+</sup>CD4<sup>+</sup>FoxP3<sup>-</sup> (CTLA-4<sup>+</sup>Tcon cells), exhausted CD8<sup>+</sup>T cells, and terminally exhausted CD8<sup>+</sup>T cells in LSCC tissues. Survival analysis was conducted to evaluate the prognostic significance of HHLA2 and these immune checkpoints or immune cell populations, employing COX regression analysis to identify independent prognostic factors.</p><p><strong>Results: </strong>Kaplan-Meier (K-M) survival curves revealed a significant association between HHLA2 expression and overall survival (OS) in LSCC. Elevated levels of HHLA2 were linked to reduced patient survival, indicating its potential as a prognostic marker (HR: 3.230, 95%CI 0.9205-11.34, P = 0.0067). Notably, increased infiltration of CD68<sup>+</sup> cells (total macrophages), STING<sup>+</sup>CD68<sup>+</sup>HLA-DR<sup>+</sup>CD163<sup>-</sup> (STING<sup>+</sup>M1 macrophages), CTLA-4<sup>+</sup>CD4<sup>+</sup>FoxP3<sup>+</sup>, CTLA-4<sup>+</sup>CD4<sup>+</sup>FoxP3<sup>-</sup>, PD-1<sup>+</sup>LAG-3<sup>+</sup>CD8<sup>+</sup>T cells, and PD-1<sup>+</sup>LAG-3<sup>+</sup>TIM-3<sup>+</sup>CD8<sup>+</sup>T cells strongly linked to poorer survival outcomes (P < 0.05). A discernible trend was observed between the levels of these immune cell populations, STING<sup>+</sup>CD68<sup>+</sup> (STING<sup>+</sup> total macrophages), CD68<sup>+</sup>HLA-DR<sup>+</sup>CD163<sup>-</sup>, STING<sup>+</sup>CD68<sup>+</sup>CD163<sup>+</sup>HLA-DR<sup>-</sup> (STING<sup>+</sup>M2 macrophages), PD-1<sup>+</sup>LAG-3<sup>-</sup>CD8<sup>+</sup>T cells, PD-1<sup>+</sup>TIM-3<sup>+</sup>CD8<sup>+</sup>T cells, and PD-1<sup>+</sup>LAG-3<sup>+</sup>TIM-3<sup>-</sup>CD8<sup>+</sup>T cells and prognosis. Importantly, multivariate COX analysis identified HHLA2 as an independent predictive factor for OS in LSCC patients (HR = 3.86, 95% CI 1.08-13.80, P = 0.038). This underscored the potential of HHLA2 as a c
{"title":"Unlocking the potential of HHLA2: identifying functional immune infiltrating cells in the tumor microenvironment and predicting clinical outcomes in laryngeal squamous cell carcinoma.","authors":"Wenjing Li, Jianqing You, Haixiang Xue, Yi Liu, Junjun Chen, Xiao Zheng, Lujun Chen, Changping Wu","doi":"10.1007/s00262-024-03791-6","DOIUrl":"10.1007/s00262-024-03791-6","url":null,"abstract":"<p><strong>Background: </strong>HHLA2 (human endogenous retrovirus-H long terminal repeat-associating protein 2) represents a recently identified member of the B7 immune checkpoint family, characterized by limited expression in normal tissues but notable overexpression in various cancer types. Nevertheless, the precise function and interaction with immune cells remain poorly understood, particularly in laryngeal squamous cell carcinoma (LSCC). This investigation endeavored to elucidate the biological significance of HHLA2 within the tumor microenvironment of human LSCC tissues and delineate the clinical relevance and functional roles of HHLA2 in LSCC pathogenesis.</p><p><strong>Methods: </strong>Through multiplexed immunohistochemistry analyses conducted on tissue microarrays sourced from LSCC patients (n = 72), the analysis was executed to assess the expression levels of HHLA2, density and spatial patterns of CD68<sup>+</sup>HLA-DR<sup>+</sup>CD163<sup>-</sup> (M1 macrophages), CTLA-4<sup>+</sup>CD4<sup>+</sup>FoxP3<sup>+</sup> (CTLA-4<sup>+</sup>Treg cells), CTLA-4<sup>+</sup>CD4<sup>+</sup>FoxP3<sup>-</sup> (CTLA-4<sup>+</sup>Tcon cells), exhausted CD8<sup>+</sup>T cells, and terminally exhausted CD8<sup>+</sup>T cells in LSCC tissues. Survival analysis was conducted to evaluate the prognostic significance of HHLA2 and these immune checkpoints or immune cell populations, employing COX regression analysis to identify independent prognostic factors.</p><p><strong>Results: </strong>Kaplan-Meier (K-M) survival curves revealed a significant association between HHLA2 expression and overall survival (OS) in LSCC. Elevated levels of HHLA2 were linked to reduced patient survival, indicating its potential as a prognostic marker (HR: 3.230, 95%CI 0.9205-11.34, P = 0.0067). Notably, increased infiltration of CD68<sup>+</sup> cells (total macrophages), STING<sup>+</sup>CD68<sup>+</sup>HLA-DR<sup>+</sup>CD163<sup>-</sup> (STING<sup>+</sup>M1 macrophages), CTLA-4<sup>+</sup>CD4<sup>+</sup>FoxP3<sup>+</sup>, CTLA-4<sup>+</sup>CD4<sup>+</sup>FoxP3<sup>-</sup>, PD-1<sup>+</sup>LAG-3<sup>+</sup>CD8<sup>+</sup>T cells, and PD-1<sup>+</sup>LAG-3<sup>+</sup>TIM-3<sup>+</sup>CD8<sup>+</sup>T cells strongly linked to poorer survival outcomes (P < 0.05). A discernible trend was observed between the levels of these immune cell populations, STING<sup>+</sup>CD68<sup>+</sup> (STING<sup>+</sup> total macrophages), CD68<sup>+</sup>HLA-DR<sup>+</sup>CD163<sup>-</sup>, STING<sup>+</sup>CD68<sup>+</sup>CD163<sup>+</sup>HLA-DR<sup>-</sup> (STING<sup>+</sup>M2 macrophages), PD-1<sup>+</sup>LAG-3<sup>-</sup>CD8<sup>+</sup>T cells, PD-1<sup>+</sup>TIM-3<sup>+</sup>CD8<sup>+</sup>T cells, and PD-1<sup>+</sup>LAG-3<sup>+</sup>TIM-3<sup>-</sup>CD8<sup>+</sup>T cells and prognosis. Importantly, multivariate COX analysis identified HHLA2 as an independent predictive factor for OS in LSCC patients (HR = 3.86, 95% CI 1.08-13.80, P = 0.038). This underscored the potential of HHLA2 as a c","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1007/s00262-024-03789-0
Shida Yan, Xing Zhang, Qiaohong Lin, Mingyuan Du, Yiqi Li, Shuai He, Jingtao Chen, Xiyuan Li, Jinxin Bei, Shuwei Chen, Ming Song
Background: Human papillomavirus (HPV) infection has become an important etiological driver of oropharyngeal squamous cell carcinoma (OPSCC), leading to unique tumor characteristics. However, the interplay between HPV-associated tumor cells and tumor microenvironment (TME) remains an enigma.
Methods: We performed a single-cell RNA-sequencing (scRNA-seq) on HPV-positive (HPV+) and HPV-negative (HPV‒) OPSCC tumors, each for three samples, and one normal tonsil tissue. Ex vivo validation assays including immunofluorescence staining, cell line co-culture, and flow cytometry analysis were used to test specific subtypes of HPV+ tumor cells and their communications with T cells.
Results: Through a comprehensive single-cell transcriptome analysis, we uncover the distinct transcriptional signatures between HPV+ and HPV‒ OPSCC. Specifically, HPV+ OPSCC tumor cells manifest an enhanced interferon response and elevated expression of the major histocompatibility complex II (MHC-II), potentially bolstering tumor recognition and immune response. Furthermore, we identify a CXCL13+CD4+ T cell subset that exhibits dual features of both follicular and pro-inflammatory helper T cells. Noteworthily, HPV+ OPSCC tumor cells embrace extensive intercellular communications with CXCL13+CD4+ T cells. Interaction with HPV+ OPSCC tumor cells amplifies CXCL13 and IFNγ release in CD4+T cells, fostering a pro-inflammatory TME. Additionally, HPV+ tumor cells expressing high MHC-II and CXCL13+CD4+ T cell prevalence are indicative of favorable overall survival rates in OPSCC patients.
Conclusions: Together, our study underscores a synergistic inflammatory immune response orchestrated by highly immunogenic tumor cells and CXCL13+CD4+ T cells in HPV+ OPSCC, offering useful insights into strategy development for patient stratification and effective immunotherapy in OPSCC.
背景:人乳头状瘤病毒(HPV)感染已成为口咽鳞状细胞癌(OPSCC)的重要病因,导致其具有独特的肿瘤特征。然而,HPV相关肿瘤细胞与肿瘤微环境(TME)之间的相互作用仍然是一个谜:我们对 HPV 阳性(HPV+)和 HPV 阴性(HPV-)的 OPSCC 肿瘤(各三个样本)和一个正常扁桃体组织进行了单细胞 RNA 序列分析(scRNA-seq)。体内外验证试验包括免疫荧光染色、细胞系共培养和流式细胞仪分析,用于检测HPV+肿瘤细胞的特定亚型及其与T细胞的通讯:通过全面的单细胞转录组分析,我们发现了HPV+和HPV- OPSCC之间不同的转录特征。具体来说,HPV+ OPSCC肿瘤细胞的干扰素反应增强,主要组织相容性复合体II(MHC-II)表达升高,这可能会增强肿瘤识别和免疫反应。此外,我们还发现了一种 CXCL13+CD4+ T 细胞亚群,它同时表现出滤泡和促炎辅助 T 细胞的双重特征。值得注意的是,HPV+ OPSCC 肿瘤细胞与 CXCL13+CD4+ T 细胞之间有着广泛的细胞间通讯。与 HPV+ OPSCC 肿瘤细胞的相互作用扩大了 CD4+T 细胞中 CXCL13 和 IFNγ 的释放,促进了促炎性 TME 的形成。此外,表达高MHC-II和CXCL13+CD4+T细胞的HPV+肿瘤细胞表明OPSCC患者的总生存率较高:总之,我们的研究强调了高免疫原性肿瘤细胞和 CXCL13+CD4+ T 细胞在 HPV+ OPSCC 中协调的协同炎症免疫反应,为 OPSCC 患者分层和有效免疫疗法的策略制定提供了有益的启示。
{"title":"Deciphering the interplay of HPV infection, MHC-II expression, and CXCL13<sup>+</sup> CD4<sup>+</sup> T cell activation in oropharyngeal cancer: implications for immunotherapy.","authors":"Shida Yan, Xing Zhang, Qiaohong Lin, Mingyuan Du, Yiqi Li, Shuai He, Jingtao Chen, Xiyuan Li, Jinxin Bei, Shuwei Chen, Ming Song","doi":"10.1007/s00262-024-03789-0","DOIUrl":"10.1007/s00262-024-03789-0","url":null,"abstract":"<p><strong>Background: </strong>Human papillomavirus (HPV) infection has become an important etiological driver of oropharyngeal squamous cell carcinoma (OPSCC), leading to unique tumor characteristics. However, the interplay between HPV-associated tumor cells and tumor microenvironment (TME) remains an enigma.</p><p><strong>Methods: </strong>We performed a single-cell RNA-sequencing (scRNA-seq) on HPV-positive (HPV<sup>+</sup>) and HPV-negative (HPV<sup>‒</sup>) OPSCC tumors, each for three samples, and one normal tonsil tissue. Ex vivo validation assays including immunofluorescence staining, cell line co-culture, and flow cytometry analysis were used to test specific subtypes of HPV<sup>+</sup> tumor cells and their communications with T cells.</p><p><strong>Results: </strong>Through a comprehensive single-cell transcriptome analysis, we uncover the distinct transcriptional signatures between HPV<sup>+</sup> and HPV<sup>‒</sup> OPSCC. Specifically, HPV<sup>+</sup> OPSCC tumor cells manifest an enhanced interferon response and elevated expression of the major histocompatibility complex II (MHC-II), potentially bolstering tumor recognition and immune response. Furthermore, we identify a CXCL13<sup>+</sup>CD4<sup>+</sup> T cell subset that exhibits dual features of both follicular and pro-inflammatory helper T cells. Noteworthily, HPV<sup>+</sup> OPSCC tumor cells embrace extensive intercellular communications with CXCL13<sup>+</sup>CD4<sup>+</sup> T cells. Interaction with HPV<sup>+</sup> OPSCC tumor cells amplifies CXCL13 and IFNγ release in CD4<sup>+</sup>T cells, fostering a pro-inflammatory TME. Additionally, HPV<sup>+</sup> tumor cells expressing high MHC-II and CXCL13<sup>+</sup>CD4<sup>+</sup> T cell prevalence are indicative of favorable overall survival rates in OPSCC patients.</p><p><strong>Conclusions: </strong>Together, our study underscores a synergistic inflammatory immune response orchestrated by highly immunogenic tumor cells and CXCL13<sup>+</sup>CD4<sup>+</sup> T cells in HPV<sup>+</sup> OPSCC, offering useful insights into strategy development for patient stratification and effective immunotherapy in OPSCC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: The time interval between neoadjuvant immunotherapy and surgery is 6 weeks for esophageal squamous cell carcinoma (ESCC), but whether delayed surgery affects prognosis remains unclear.
Methods: Clinical data of locally advanced ESCC who underwent neoadjuvant immunotherapy followed by esophagectomy from November 2019 to December 2022 were collected. The surgery outcomes and prognosis were compared between short-interval (time to surgery ≤ 6 weeks) and long-interval groups (time to surgery > 6 weeks).
Results: 152 patients were enrolled totally, with a ratio of 91:61 between short-interval and long-interval groups. The rate of pathological complete response in the short-interval and long-interval groups were 34.1% and 24.6% (P = 0.257). Delayed surgery did not have a significantly impact on the number of lymph node dissections (P = 0.133), operative duration (P = 0.689), blood loss (P = 0.837), hospitalization duration (P = 0.293), chest drainage duration (P = 0.886) and postoperative complications (P > 0.050). The 3-year Overall survival (OS) rates were 85.10% in the short-interval group, and 82.07% in the long-interval group (P = 0.435). The 3-year disease-free survival (DFS) rates were 83.41% and 70.86% in the two groups (P = 0.037). Subgroup analysis revealed that patients with a favorable response to immunotherapy (tumor regression grade 0) exhibited inferior 3-year OS (long-interval vs. short-interval: 51.85% vs. 91.08%, P = 0.035) and DFS (long-interval vs. short-interval: 47.40% vs. 91.08%, P = 0.014) in the long-interval group.
Conclusions: Delayed surgery after neoadjuvant immunotherapy does not further improve pathological response; instead, it resulted in a poorer DFS. Especially for patients with a favorable response to immunotherapy, delayed surgery increases the risk of mortality and recurrence.
{"title":"Impact of the interval between neoadjuvant immunotherapy and surgery on prognosis in esophageal squamous cell carcinoma (ESCC): a real-world study.","authors":"Guozhen Yang, Yutong Hong, Xiaomin Zhang, Chufeng Zeng, Linyu Tan, Xu Zhang","doi":"10.1007/s00262-024-03787-2","DOIUrl":"10.1007/s00262-024-03787-2","url":null,"abstract":"<p><strong>Background: </strong>The time interval between neoadjuvant immunotherapy and surgery is 6 weeks for esophageal squamous cell carcinoma (ESCC), but whether delayed surgery affects prognosis remains unclear.</p><p><strong>Methods: </strong>Clinical data of locally advanced ESCC who underwent neoadjuvant immunotherapy followed by esophagectomy from November 2019 to December 2022 were collected. The surgery outcomes and prognosis were compared between short-interval (time to surgery ≤ 6 weeks) and long-interval groups (time to surgery > 6 weeks).</p><p><strong>Results: </strong>152 patients were enrolled totally, with a ratio of 91:61 between short-interval and long-interval groups. The rate of pathological complete response in the short-interval and long-interval groups were 34.1% and 24.6% (P = 0.257). Delayed surgery did not have a significantly impact on the number of lymph node dissections (P = 0.133), operative duration (P = 0.689), blood loss (P = 0.837), hospitalization duration (P = 0.293), chest drainage duration (P = 0.886) and postoperative complications (P > 0.050). The 3-year Overall survival (OS) rates were 85.10% in the short-interval group, and 82.07% in the long-interval group (P = 0.435). The 3-year disease-free survival (DFS) rates were 83.41% and 70.86% in the two groups (P = 0.037). Subgroup analysis revealed that patients with a favorable response to immunotherapy (tumor regression grade 0) exhibited inferior 3-year OS (long-interval vs. short-interval: 51.85% vs. 91.08%, P = 0.035) and DFS (long-interval vs. short-interval: 47.40% vs. 91.08%, P = 0.014) in the long-interval group.</p><p><strong>Conclusions: </strong>Delayed surgery after neoadjuvant immunotherapy does not further improve pathological response; instead, it resulted in a poorer DFS. Especially for patients with a favorable response to immunotherapy, delayed surgery increases the risk of mortality and recurrence.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1007/s00262-024-03788-1
Rong Duan, Philip Milton, Chutamath Sittplangkoon, Xin Liu, Zhining Sui, Brendan F Boyce, Zhenqiang Yao
Background: Chimeric antigen receptor (CAR)-T cells have been used to treat blood cancers by producing a wide variety of cytokines. However, they are not effective in treating solid cancers and can cause severe side-effects, including cytokine release syndrome. TNFα is a tumoricidal cytokine, but it markedly increases the protein levels of cIAP1 and cIAP2, the members of inhibitor of apoptosis protein (IAP) family of E3 ubiquitin ligase that limits caspase-induced apoptosis. Degradation of IAP proteins by an IAP antagonist does not effectively kill cancer cells but enables TNFα to strongly induce cancer cell apoptosis. It would be a promising approach to treat cancers by targeted delivery of TNFα through an inactive adoptive cell in combination with an IAP antagonist.
Methods: Human dendritic cells (DCs) were engineered to express a single tumoricidal factor, TNFα, and a membrane-anchored Mucin1 antibody scFv, named Mucin 1 directed DCs expressing TNFα (M-DCsTNF). The efficacy of M-DCsTNF in recognizing and treating breast cancer was tested in vitro and in vivo.
Results: Mucin1 was highly expressed on the surface of a wide range of human breast cancer cell lines. M-DCsTNF directly associated with MDA-MB-231 cells in the bone of NSG mice. M-DCsTNF plus an IAP antagonist, SM-164, but neither alone, markedly induce MDA-MB-231 breast cancer cell apoptosis, which was blocked by TNF antibody. Importantly, M-DCsTNF combined with SM-164, but not SM-164 alone, inhibited the growth of patient-derived breast cancer in NSG mice.
Conclusion: An adoptive cell targeting delivery of TNFα combined with an IAP antagonist is a novel effective approach to treat breast cancer and could be expanded to treat other solid cancers. Unlike CAR-T cell, this novel adoptive cell is not activated to produce a wide variety of cytokines, except for additional overexpressed TNF, and thus could avoid the severe side effects such as cytokine release syndrome.
{"title":"Chimeric antigen receptor dendritic cells targeted delivery of a single tumoricidal factor for cancer immunotherapy.","authors":"Rong Duan, Philip Milton, Chutamath Sittplangkoon, Xin Liu, Zhining Sui, Brendan F Boyce, Zhenqiang Yao","doi":"10.1007/s00262-024-03788-1","DOIUrl":"10.1007/s00262-024-03788-1","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor (CAR)-T cells have been used to treat blood cancers by producing a wide variety of cytokines. However, they are not effective in treating solid cancers and can cause severe side-effects, including cytokine release syndrome. TNFα is a tumoricidal cytokine, but it markedly increases the protein levels of cIAP1 and cIAP2, the members of inhibitor of apoptosis protein (IAP) family of E3 ubiquitin ligase that limits caspase-induced apoptosis. Degradation of IAP proteins by an IAP antagonist does not effectively kill cancer cells but enables TNFα to strongly induce cancer cell apoptosis. It would be a promising approach to treat cancers by targeted delivery of TNFα through an inactive adoptive cell in combination with an IAP antagonist.</p><p><strong>Methods: </strong>Human dendritic cells (DCs) were engineered to express a single tumoricidal factor, TNFα, and a membrane-anchored Mucin1 antibody scFv, named Mucin 1 directed DCs expressing TNFα (M-DCs<sup>TNF</sup>). The efficacy of M-DCs<sup>TNF</sup> in recognizing and treating breast cancer was tested in vitro and in vivo.</p><p><strong>Results: </strong>Mucin1 was highly expressed on the surface of a wide range of human breast cancer cell lines. M-DCs<sup>TNF</sup> directly associated with MDA-MB-231 cells in the bone of NSG mice. M-DCs<sup>TNF</sup> plus an IAP antagonist, SM-164, but neither alone, markedly induce MDA-MB-231 breast cancer cell apoptosis, which was blocked by TNF antibody. Importantly, M-DCs<sup>TNF</sup> combined with SM-164, but not SM-164 alone, inhibited the growth of patient-derived breast cancer in NSG mice.</p><p><strong>Conclusion: </strong>An adoptive cell targeting delivery of TNFα combined with an IAP antagonist is a novel effective approach to treat breast cancer and could be expanded to treat other solid cancers. Unlike CAR-T cell, this novel adoptive cell is not activated to produce a wide variety of cytokines, except for additional overexpressed TNF, and thus could avoid the severe side effects such as cytokine release syndrome.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1007/s00262-024-03775-6
Ramya Muddasani, Neel Talwar, Isa Mambetsariev, Jeremy Fricke, Mercury Lin, Daniel Schmolze, Andrew Yue, Amna Rizvi, Ravi Salgia
Background: Acute kidney injury (AKI) has been well described as a complication of immune checkpoint inhibitor therapy. We present a series of patients, the majority with lung adenocarcinoma, who developed AKI while actively receiving immune checkpoint inhibitors.
Methods: This is a retrospectively analyzed clinical case series of six patients treated at City of Hope Comprehensive Cancer Center. Data were collected on gender, age, ethnicity, comorbidities, concomitant medications, type of malignancy, treatments, and renal function. All patients underwent renal biopsy for classification of the mechanism of AKI. Comprehensive genomic profiling (CGP) was performed on tumor tissue for all patients.
Results: Patterns of AKI included acute interstitial nephritis and acute tubular necrosis. Contributing factors included the use of concomitant medications known to contribute to AKI. All but two patients had full resolution of the AKI with the use of steroids. There were several mutations found on CGP that was notable including an Exon 20 insertion as well as multiple NF1 and TP53 mutations. There was high PD-L1 expression on tumor tissue noted in two out of six patients. In addition to AKI, a subset of patients had proteinuria with biopsies revealing corresponding glomerular lesions of minimal change disease and focal and segmental glomerulosclerosis.
Conclusions: Our case series demonstrates that AKI from immune checkpoint inhibitors has a variable presentation that may require an individualized treatment approach. Further studies are needed to identify biomarkers that may help identify those at risk and guide the management of this condition.
背景:急性肾损伤(AKI)作为免疫检查点抑制剂治疗的一种并发症已被广泛描述。我们介绍了一系列在积极接受免疫检查点抑制剂治疗期间出现急性肾损伤的患者,其中大部分患者为肺腺癌患者:这是一个回顾性分析的临床病例系列,涉及在希望之城综合癌症中心接受治疗的六名患者。收集的数据包括性别、年龄、种族、合并症、伴随药物、恶性肿瘤类型、治疗方法和肾功能。所有患者都接受了肾活检,以便对 AKI 的机制进行分类。对所有患者的肿瘤组织进行了全面基因组分析(CGP):结果:AKI的模式包括急性间质性肾炎和急性肾小管坏死。诱发因素包括同时使用已知会导致 AKI 的药物。除两名患者外,所有患者在使用类固醇后都完全缓解了AKI。CGP上发现了几个值得注意的突变,包括一个外显子20插入以及多个NF1和TP53突变。六名患者中有两名患者的肿瘤组织中出现了 PD-L1 高表达。除了 AKI 外,部分患者还出现蛋白尿,活检显示相应的肾小球病变,包括微小病变、局灶性和节段性肾小球硬化:我们的系列病例表明,免疫检查点抑制剂引起的 AKI 表现各异,可能需要个体化的治疗方法。还需要进一步研究来确定生物标志物,以帮助识别高危人群并指导该病症的治疗。
{"title":"Clinical features associated with immune checkpoint inhibitor nephritis: a single-center clinical case series.","authors":"Ramya Muddasani, Neel Talwar, Isa Mambetsariev, Jeremy Fricke, Mercury Lin, Daniel Schmolze, Andrew Yue, Amna Rizvi, Ravi Salgia","doi":"10.1007/s00262-024-03775-6","DOIUrl":"10.1007/s00262-024-03775-6","url":null,"abstract":"<p><strong>Background: </strong>Acute kidney injury (AKI) has been well described as a complication of immune checkpoint inhibitor therapy. We present a series of patients, the majority with lung adenocarcinoma, who developed AKI while actively receiving immune checkpoint inhibitors.</p><p><strong>Methods: </strong>This is a retrospectively analyzed clinical case series of six patients treated at City of Hope Comprehensive Cancer Center. Data were collected on gender, age, ethnicity, comorbidities, concomitant medications, type of malignancy, treatments, and renal function. All patients underwent renal biopsy for classification of the mechanism of AKI. Comprehensive genomic profiling (CGP) was performed on tumor tissue for all patients.</p><p><strong>Results: </strong>Patterns of AKI included acute interstitial nephritis and acute tubular necrosis. Contributing factors included the use of concomitant medications known to contribute to AKI. All but two patients had full resolution of the AKI with the use of steroids. There were several mutations found on CGP that was notable including an Exon 20 insertion as well as multiple NF1 and TP53 mutations. There was high PD-L1 expression on tumor tissue noted in two out of six patients. In addition to AKI, a subset of patients had proteinuria with biopsies revealing corresponding glomerular lesions of minimal change disease and focal and segmental glomerulosclerosis.</p><p><strong>Conclusions: </strong>Our case series demonstrates that AKI from immune checkpoint inhibitors has a variable presentation that may require an individualized treatment approach. Further studies are needed to identify biomarkers that may help identify those at risk and guide the management of this condition.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1007/s00262-024-03744-z
Qin Wang, Fan Tong, Li Qiao, Liang Qi, Yi Sun, Yahui Zhu, Jiayao Ni, Juan Liu, Weiwei Kong, Baorui Liu, Juan Du
Purpose: To assess the efficacy and safety of concurrent hypofractionated radiotherapy plus anti-PD-1 antibody and SOX chemotherapy in the treatment of metastatic pancreatic cancer (mPC) after failure of first-line chemotherapy.
Methods: Patients with pathologically confirmed mPC who failed standard first-line chemotherapy were enrolled. The patients were treated with a regimen of hypofractionated radiotherapy, SOX chemotherapy, and immune checkpoint inhibitors at our institution. We collected the patients' clinical information and outcome measurements. The median progression-free survival (mPFS) was the primary endpoint of the study, followed by disease control rate (DCR), objective response rate (ORR), median overall survival (mOS) and safety. Exploratory analyses included biomarkers related to the benefits.
Results: Between February 24, 2021, and August 30, 2023, twenty-five patients were enrolled in the study, and twenty-three patients who received at least one dose of the study agent had objective efficacy evaluation. The mPFS was 5.48 months, the mOS was 6.57 months, and the DCR and ORR were 69.5% and 30.4%, respectively. Among the seven patients who achieved a PR, the median duration of the response was 7.41 months. On-treatment decreased serum CA19-9 levels were associated with better overall survival. Besides, pretreatment inflammatory markers were associated with tumor response and survival.
Conclusions: Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with these combination therapies in patients with refractory mPC. On-treatment decreased serum CA19-9 levels and pretreatment inflammatory markers platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), lactate dehydrogenase (LDH) might be biomarkers related to clinical benefits.
Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=130211 , identifier: ChiCTR2100049799, date of registration: 2021-08-09.
{"title":"Hypofractionated radiotherapy plus PD-1 antibody and SOX chemotherapy as second-line therapy in metastatic pancreatic cancer: a single-arm, phase II clinical trial.","authors":"Qin Wang, Fan Tong, Li Qiao, Liang Qi, Yi Sun, Yahui Zhu, Jiayao Ni, Juan Liu, Weiwei Kong, Baorui Liu, Juan Du","doi":"10.1007/s00262-024-03744-z","DOIUrl":"10.1007/s00262-024-03744-z","url":null,"abstract":"<p><strong>Purpose: </strong>To assess the efficacy and safety of concurrent hypofractionated radiotherapy plus anti-PD-1 antibody and SOX chemotherapy in the treatment of metastatic pancreatic cancer (mPC) after failure of first-line chemotherapy.</p><p><strong>Methods: </strong>Patients with pathologically confirmed mPC who failed standard first-line chemotherapy were enrolled. The patients were treated with a regimen of hypofractionated radiotherapy, SOX chemotherapy, and immune checkpoint inhibitors at our institution. We collected the patients' clinical information and outcome measurements. The median progression-free survival (mPFS) was the primary endpoint of the study, followed by disease control rate (DCR), objective response rate (ORR), median overall survival (mOS) and safety. Exploratory analyses included biomarkers related to the benefits.</p><p><strong>Results: </strong>Between February 24, 2021, and August 30, 2023, twenty-five patients were enrolled in the study, and twenty-three patients who received at least one dose of the study agent had objective efficacy evaluation. The mPFS was 5.48 months, the mOS was 6.57 months, and the DCR and ORR were 69.5% and 30.4%, respectively. Among the seven patients who achieved a PR, the median duration of the response was 7.41 months. On-treatment decreased serum CA19-9 levels were associated with better overall survival. Besides, pretreatment inflammatory markers were associated with tumor response and survival.</p><p><strong>Conclusions: </strong>Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with these combination therapies in patients with refractory mPC. On-treatment decreased serum CA19-9 levels and pretreatment inflammatory markers platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), lactate dehydrogenase (LDH) might be biomarkers related to clinical benefits.</p><p><strong>Clinical trial registration: </strong>https://www.chictr.org.cn/showproj.html?proj=130211 , identifier: ChiCTR2100049799, date of registration: 2021-08-09.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1007/s00262-024-03790-7
Ravit Geva, Maria Vieito, Jorge Ramon, Ruth Perets, Manuel Pedregal, Elena Corral, Bernard Doger, Emiliano Calvo, Jorge Bardina, Elena Garralda, Regina J Brown, James G Greger, Shujian Wu, Douglas Steinbach, Tsun-Wen Sheena Yao, Yu Cao, Josh Lauring, Ruchi Chaudhary, Jaymala Patel, Bharvin Patel, Victor Moreno
Background: JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors.
Methods: Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS).
Results: Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry.
Conclusion: JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740).
{"title":"Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors.","authors":"Ravit Geva, Maria Vieito, Jorge Ramon, Ruth Perets, Manuel Pedregal, Elena Corral, Bernard Doger, Emiliano Calvo, Jorge Bardina, Elena Garralda, Regina J Brown, James G Greger, Shujian Wu, Douglas Steinbach, Tsun-Wen Sheena Yao, Yu Cao, Josh Lauring, Ruchi Chaudhary, Jaymala Patel, Bharvin Patel, Victor Moreno","doi":"10.1007/s00262-024-03790-7","DOIUrl":"10.1007/s00262-024-03790-7","url":null,"abstract":"<p><strong>Background: </strong>JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors.</p><p><strong>Methods: </strong>Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS).</p><p><strong>Results: </strong>Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry.</p><p><strong>Conclusion: </strong>JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740).</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}